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A new kinetic-photometric method for determination of carbimazole

A new kinetic-photometric method for determination of carbimazole
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  A New Kinetic-Photometric Method for Determination of Carbimazole Mohsen Barzegar  a *, Abdolvahed Rahmani  b , Ali Jabbari c and Mir Fazlollah Mousavi d a  Department of Food Sciences and Technology, Tarbiat Modarres University, P. O. Box: 14115-336, Tehran, Iran  b  Department of Chemistry, Hormozgan University, Bandar Abbas, Iran c  Department of Chemistry, K. N. Toosi University, Tehran, Iran d  Department of Chemistry, Tarbiat Modarres University, Tehran, Iran A new kinetic photometric method for determination of carbimazole (CBZ) is described. The proposedmethod is simple, rapid, inexpensive and sensitive for the determination of CBZ in pure and tablet forms. Thismethod is based on the inhibitory effect of carbimazole on the palladium(II)-catalyzed reaction between neu-tral red (NR) and hypophosphite (HP) ions. The effect of various parameters such as dye, hypophosphite, andPd(II)concentrations,pH,ionicstrength,andtemperaturewereoptimized.Thecalibrationgraphwaslinearinthe range 0.04-0.30 ppm (n = 9, r = 0.9972) and the detection limit was 0.02 ppm. The relative standard devia-tion of the developed method was 0.70% (n = 10). The proposed method was applied for the determination of carbimazole in pure and tablet forms. Keywords:  Carbimazole; Kinetic photometric method; Palladium; Inhibition; Neutral red. INTRODUCTION Carbimazole 3-ethoxycarbonyl-1-methyl-2,3-dihydro-1H-imidazole-2-thione (Scheme I) is an anti-thyroid agentthat depresses the formation of thyroid hormones. 1 This drug and other anti-thyroid agents being the thiourea pharmacophore, inhibit the first step in the pathway of thy-roid hormone biosynthesis which is the incorporation of oxi-dized iodide into tyrosine residues in the large thyroid hor-mone precursor molecule, thyroglobulin. The determinationof carbimazole (CBZ) is important in different areas such asclinical chemistry, nutrition and pharmaceutical formula-tions.Several analytical procedures have been described for the analysis of CBZ: an indirect bromometric titration, 2 a di-rect titration method, 3  potentiometric, 4,5 voltammetric, 6 chro-matographic, 7-9 spectrophotometric, 10-13  polarographic, 14 andfluorometric. 15 Some of the published methods suffer interferencefrom tablet base, while others are not simple for routine anal-ysis,astheyneedsophisticatedinstrumentsandexpensivere-agents. Therefore, it was considered worthwhile to develop arapid, simple and accurate procedure suitable for applicationin quality control laboratories.In this paper, a detailed study of the appropriate condi-tions for the inhibition effect of CBZ on the reduction of neu-tral red (NR) by hypophosphite (HP) in the presence of palla-dium(II) was performed. The reaction was monitored photo-metrically at the maximum wavelength of the NR (530 nm)while measuring the change in the absorbance with time. EXPERIMENTALReagents All chemicals were of analytical-reagent grade and thesolutions were prepared with doubly distilled water. Workingsolutions of lower concentrations were prepared by appropri-ate dilution of the respective stock solutions prior to use.Palladiumchloride(1000ppm,0.1670g)wasdissolvedin 2.0 mL concentrated HCl (Merck) and the solution wastransferred into a 100 mL standard flask and then diluted to  Journal of the Chinese Chemical Society ,  2004 ,  51 , 363-366  363 * Corresponding author. E-mail:  NNSMe COOEt Scheme I  Carbimazole  volume with water to make Pd stock solution. Neutral red so-lution (2    10 -4 M) was prepared by dissolving 0.0290 g of  NR (Merck) and diluting to 500 mL in a calibrated flask.Hypophosphite (2 M) solution was prepared by dissolving20.8180 g of potassium hypophosphite (Merck) in 100 mL of water.The purity of the carbimazole, kindly supplied byPoursina Pharmaceutical Company (Tehran, Iran), was provedto be 100.4% according to BP. 16 The stock solution was pre- pared by dissolving 0.0100 g of CBZ with water and dilutingto 100 mL. The pharmaceutical formulation “carbimazole”tablets (5 mg) were offered by Poursina PharmaceuticalCompany. Apparatus A 662 probe-type photometer (Metrohm), and a Grantthermostatically controlled bath/circulator (Grant Instru-ment, Ltd., Cambridge) were used. During all experiments,solutions were stirred with a magnetic stirrer (Zag-ChemieCo., Ltd., Tehran, Iran). All pH measurements were carriedout with a Metrohm pH-meter model 691. Procedures For calibration curve: After a suitable aliquot of solu-tion containing 0.6-4.5   g carbimazole was transferred into a15-mL volumetric flask, 3.5 mL of 2.0 M hypophosphite, and3.0 mL of 2.0    10 -4 M neutral red solution were added. Thesolution was diluted to 15 mL with water. After mixing well,the aliquot was transferred into a glass cell (thermostated at25  C). Then, the A-t curve was recorded just after the instan-taneous addition of Pd(II) using a microsyringe. The reactionwas monitored photometrically by measuring the absorbanceat 530 nm. The time scan was recorded by computer-inter-faced probe-type. The cell was cleaned after use by immer-sion into HNO 3  (6 M) in order to remove any trace of Pd(0)absorbed on to the wall.Assay of CBZ tablet: Ten tablets were weighed andcrushed in a mortar. A mass of powder equivalent to the aver-age mass of one tablet (5 mg) was dissolved in 50 mL water.The solution was filtered through a Millipore filter, and thefiltrate was diluted with water in a 100 mL calibrated flask. A2.0 mL aliquot of solution was diluted to 50 mL with water and the proposed procedure was applied. All the necessary precautions were taken to guard against the possible degrada-tion of CBZ. These precautions included the use of freshly prepared solution at low temperature and protection fromlight. RESULTS AND DISCUSSION Our previous work  17 has demonstrated that in the pres-ence of a trace amount of Pd(II), hypophosphite reduces neu-tral red rapidly. A report 11 has shown that Pd(II) reacts withCBZ and methimazole to produce yellow complexes. There-fore, carbimazole decreases the catalytic effect of Pd(II) onthe reaction of the NR-HP system. The reaction rate of thecatalyzed reaction decreased with increasing the amounts of carbimazole and time required for the absorbance to decreaseto a predetermined value increased. The reaction was moni-tored photometrically by measuring the time required for theabsorbance of the NR to decrease by 0.1 (at  max  = 530 nm) bymeans of variable time method. Effect of variables To obtain the maximum sensitivity in the determinationof CBZ, we investigated the effect of several variables on therate of catalyzed and inhibited catalyzed reactions, as fol-lows.The effect of pH on the catalyzed and inhibited cata-lyzed reaction was studied in the range of 2.0-6.0 and the re-sults are shown in Fig. 1. As can be seen, the inhibitory effectof CBZ reaches a maximum and is constant over the pH range4.1-5.0. All subsequent investigations were performed at pH= 4.6.The influence of the hypophosphite concentration wasstudied over the range 0.11-0.56 M. The rates of catalyzedand inhibited reactions increase with increasing concentra-tion of HP up to 0.39 M, above which they decrease slightly.The effect of neutral red was investigated in the range1.1  -5 -5.6  -5 M. Fig. 2 shows the percentage of inhibi-tion (I%) versus different NR concentrations. A concentra-tion of 3.3    -5 M, at which the inhibitory effect of CBZ is 364  J. Chin. Chem. Soc., Vol. 51, No. 2, 2004  Barzegar et al. 05101520251.5 2.5 3.5 4.5 5.5 6.5 pH     %    I Fig. 1. Effect of pH on the percent of inhibition. Con-ditions: [NR] = 3.3    -5 M; [Pd] = 1.1 ppm;[HP] = 0.39 M; T = 25   C.  maximum, was selected.TheinfluenceofionicstrengthbyusingKClsolution(2M) on the reaction rate was studied in the concentration rangeof 0.0-0.9 M. The percentage of inhibition remains constantwhen the KCl concentration is in the range of 0.0-0.34 M anddecreases with the concentration larger than 0.34 M.An important variable is concentration of Pd(II). Theinhibitory effect of the antithyroid drug decreases when theconcentration of Pd(II) increases; see Fig. 3, which shows theresults obtained in the presence of 0.14 ppm of CBZ and anincreasing amount of Pd(II). Moreover, the linear range of CBZ concentrations that can be determined and the slope of the calibration graph obtained under optimum conditions de- pendontheconcentrationofcatalyst.Aconcentrationof0.45 ppm of Pd(II) was selected as the most suitable concentra-tion.The effect of temperature on the rate of catalyzed andinhibited reaction was studied in the range 15-55   C. The re-sults show that 25   C is best, since at higher temperatures theinhibition effect of CBZ is decreased, causing great increasein the rate. Thus, 25   C was used as the most convenient tem- perature. Features of the analytical method The method used to construct calibration plot in thekinetic determination of inhibitors, as described by Perez-Bendito, 18 was commonly run by plotting the percentage of inhibition as a function of the inhibitor concentration. Under the optimum experimental conditions a calibration plot wasobtained in the range 0.04-0.30 ppm of carbimazole.In the concentration range 0.04-0.30 ppm of CBZ, a re-gression equation, I% = 40.58 + 0.20 C, with a correlation co-efficient of 0.9972 (n = 9) was obtained, where C is the con-centration of carbimazole (ppm). The theoretical limit of de-tection 19 was 0.02 ppm of CBZ. The precision (RSD%) of thedeveloped method was 0.70% (n = 10) for 0.15 ppm of car- bimazole. Study on the interference from other substances Under the optimum experimental conditions to studythe selectivity of the method, the effect of frequently encoun-tered excipients and additives in the pharmaceutical dosageform of CBZ was studied by adding different amounts of pos-sible interferences to a sample containing 0.17 ppm of CBZ. No interference was observed from the presence of glucose,lactose, starch or carboxymethyl cellulose (120-fold). Application To evaluate the analytical applicability of the method,the developed method was applied to the determination of CBZ in carbimazole tablets. For comparison purposes, thereference method adopted in the BP 16 was applied using spec-trophotometric determination at 291 nm. Table 1 shows theresults obtained by proposed and reference methods. Ap- plying the F-test and the t-test at the 95% confidence levelcompared the results obtained in both methods. The calcu-lated F and t values did not exceed the theoretical values (F =5.05, t = 2.57) indicating that there is no significant differ-ence between the two methods with respect to accuracy. CONCLUSION The kinetic-photometric method proposed for the de-A New Kinetic-Photometric Method for Determination of Carbimazole  J. Chin. Chem. Soc., Vol. 51, No. 2, 2004  365 05101520250 1 2 3 4 5 6 C (M) x 10 5     %    I Fig. 2. Influence of neutral red concentration on the percent of inhibition. Conditions: [Pd] = 1.1 ppm; [HP] = 0.39 M; T = 25   C. 0204060800 0.5 1 1.5 2 C (ppm)     %    I Fig. 3. Effect of Pd(II) concentration on the percent of inhibition. Conditions: [NR] = 3.3    10 -5 M;[HP] = 0.39 M; T = 25   C.Table 1. Determination of Carbimazole in Tablet Form in mg per Tablet a Declared content Reference method Proposed method RSD%5 4.90    0.10 4.93    0.04 0.81 a Average of six determinations    S.D.  termination of CBZ is simple, sensitive, inexpensive, andrapid. This method is comparable in accuracy and precisionwith the reference method described in the cited reference.The developed method is suitable for the analysis of theCBZ in pharmaceuticals, as there are no interferences fromthe excipients normally found in commercial preparations. ACKNOWLEDGEMENT The authors are grateful to the Tarbiat Modarres Uni-versity Research Council for financial support and PoursinaPharmaceutical Company for supplying pure and tabletforms of carbimazole.Received May 27, 2003. REFERENCES 1. Goodman, G. A.; Goodman, L. S.; Rall, T. W.; Murad, F.  The PharmacologicalBasisofTherapeutics ;MacmillanPublica-tion Co.: New York, 1995.2. El-Bardicy, M. G.; El-Saharty, Y. S.; Tawakkol, M. S. Talanta  1993 ,  40 , 577.3. Sriramam, K.; Sastry, N. R.; Sastry, B. V. S.; Prasuna, G. N.L.  Indian Drugs  1984 ,  21 , 520.4. Pinzauti, S.; Dal Piaz, V.; La Porta, E.  Farmaco-Ed. Pr  . 1973 ,  28 , 396.5. Ciesielski, W.; Krenc, A.  Anal. Lett.  2000 ,  33 , 1545.6. 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